Juxtaposed laminated arrangement

ABSTRACT

A dispenser is enclosed for delivering a beneficial agent to an enviroment of use. The dispenser comprising a wall that surrounds an internal space comprising a first mean in the dispenser for changing from a dispenser state to an environment of use state on leaving the dispenser, a beneficial agent in the first means, and a second means in the dispenser for aiding in displacing the first means from the dispenser.

FIELD OF THE INVENTION

This invention pertains to both a novel and useful dispenser. Moreparticularly, the invention relates to a dispenser comprising asemipermeable wall that surrounds, at least in part, a lumen comprisinga displaceable matrix comprising solid state properties and contains abeneficial agent. The lumen contains also an expandable push member forurging the displaceable matrix from the dispenser. In a presentlypreferred embodiment the dispenser comprises a mouth with an openingsubstantially equal to the cross-sectional area of the lumen fordelivering the displaceable matrix comprising the drug to theenvironment of use.

BACKGROUND OF THE INVENTION

Dispensers for delivering a beneficial agent to the environment of useare known to the prior art. For examle, one dispenser is disclosed inU.S. Pat. No. 3,995,632 issued to Nakano, Higuchi and Hussain. Thispatent discloses a dispenser comprising a saturated solution ofmagnesium sulfate that pushes against a melted composition. The meltedcomposition is squeezed through a passageway from the dispenser. In U.S.Pat. No. 4,251,506 issued to patentee Laby, a device is disclosedconsisting of a controlled release composition for administration of atherapeutic agent to a ruminant. The patent discloses in detail a springfor pushing a composition from the dispenser. The use of a spring as adriving force limits the practical use of the device as the drivingforce of a spring diminished by the distance through which the springoperates. For this device drug delivery decreases over time as thespring elongates and concurrently weakens. The delivery rate isinfluenced also by the nature of the composition and its interactionwith fluid at the interfaced environment of use. The interface providesexterior mechanical action that controls drug release by the environmentand not by the device. Another dispenser is disclosed in U.S. Pat. No.4,327,725 by inventors Cortese and Theeuwes. The dispenser disclosed inthis patent comprises a hydrogel that urges an aqueous formulationthrough a passageway from the dispenser. In U.S. Pat. No. 4,350,271issued to Eckenhoff, a dispenser is disclosed comprising a waterswellable composition that pushes a lipophilic fluid from the dispenser.U.S. Pat. No. 4,612,008 issued to Wong, Barclay, Deters and Theeuwesdiscloses a dispenser wherein an expanding polymer urges a drugformulation comprising an aqueous osmotically active solution from thedispenser. Another dispenser is disclosed by patentees Eckenhoff,Cortese and Landrau in U.S. Pat. No. 4,595,583. The dispenser disclosedin this patent comprises an expandable aqueous activated osmopolymerthat urges a heat responsive composition through an orifice from thedispenser.

The dispenser of the prior art presented above represents an outstandingand pioneering advancement in the dispensing art, and they areadditionally useful for dispensing innumerable beneficial agents to anenvironment of use. Now, this present invention has unexpectedlydiscovered that a dispenser can be made available comprising a novel andunobvious dispensing means unknown heretofore the delivery a beneficialagent to an environment of use. That is, it has now been discovered thata dispenser can be provided comprising means for delivering abio-affecting beneficial agent in a substantially formulated solid format a kinetically controlled rate substantially equal to its kinetic rateof release from the dispenser. The dispenser thereby makes available toa beneficial agent receptor controlled and constant prolonged deliveryof a beneficial agent according to a preselected built-in optimalprogram of beneficial agent presentation.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation, it is a principle objectof this invention to provide a dispenser comprising novel means for thecontrolled delivery of a beneficial agent at a rate substantiallyequivalent to its dispenser-controlled rate of release from thedispenser over time.

Another object to the present invention is to provide a dispenser thatdelivers a beneficial agent in a solid state that erodes at a controlledrate in a fluid environment of use as it is dispensed from thedispenser.

Another object of the present invention is to provide a dispenser thatdelivers a beneficial agent in a solid state carrier that diffusestherefrom at a controlled rate in a fluid environment of use as thecarrier is rate-displaced from the dispenser.

Another object of the present invention is to provide a dispensercomprising a carrier in a substantially solid therapeutically acceptableform containing a beneficial agent that is leached from the carrier in afluid environment of use as the carrier is rate displaced from thedispenser.

Another object of the present invention is to provide a dispensercomprising a carrier selected from the group consisting of a solid andsemisolid carrier containing a beneficial agent that is delivered fromthe carrier by osmotic bursting into a fluid environment of use overtime.

Another object of the invention is to provide a dispenser comprising adrug that is soluble or insoluble in an erodible solid or semisolidcarrier and is released therefrom by the erosion of the carrier.

Another object of the present invention is to provide a dispenser withhigh drug loading that is self-contained, self-starting and self-poweredin a fluid environment of use.

Another object of the present invention is to provide a dispenser thatis easy to manufacture, economical to make, and can be used fordispensing a beneficial agent to a warm-blooded animal at a controlledrate over time.

Another object of the present invention is to provide a dispensercomprising an internal capsule arrangement that makes it easier tomanufacture the dispenser at a reduced cost thereby extending theusefulness of the dispenser for treating humans and domestic animals.

Another object of the present invention is to provide a dispensercomprising an internal lumen containing a carrier comprising acontinuous, uninterrupted linear body member symmetrical with the axisof the lumen, and which carrier is displaced at a continuous,uninterrupted rate from the lumen over time.

Another object of the present invention is to provide a dispensercomprising a wall that surrounds a lumen with a mouth in the wall havingan opening substantially equal to the cross-sectional area of the lumen,and which lumen houses a continuous body member that is urged throughthe mouth for delivering a beneficial agent to an environment of use andby doing so, a solid fonmulation of insoluble drug up to 92% can bedisbursed in the carrier and delivered to the environment of use.

Another object of the present invention is to provide a dispensercomprising a capsule lumen containing a continuous body member thatextends the length of the lumen except for an expandable driving memberfor urging the body member from the lumen, a semipermeable wall thatsurrounds the capsule, and an opening having substantially the samedimensions as the lumen for dispensing the body member from thedispenser.

Another object of the invention is to provide a dispenser comprising asemipermeable wall that surrounds in at least a part an internal lumen,which lumen contains a carrier that initially occupies a major portionof the lumen except for a driving member and an optional densifier, withthe dispenser delivering a beneficial agent by the combinedphysical-chemical operations of the driving member urging thedisplaceable carrier through an opening in the wall to the environmentof use.

Another object of the invention is to provide a dispenser comprising adense member for keeping the dispenser in the rumen over time, whereinthe dispenser administers a complete phanmaceutical dosage regimen for aprolonged period of time, the use of which dispenser requiresintervention only for initiation of the regimen.

Another object of the invention is to provide a delivering systemmanufactured as a dispenser comprising a carrier for a drug wherein thecarrier keeps its physical and chemical integrity during its stay in thedispenser and changes its physical and/or chemical integrity on itsdisplacement from the dispenser into a fluid environment of ue.

Another object of the present invention is to provide a drug deliverysystem that can deliver a beneficial drug contained in a pharmaceuticalcarrier that maintains its structure within the delivery system andchanges its structure on its delivery into the gastrointestinal tractwherein the pharmaceutical carrier dispenses the drug.

Another object of the present invention is to provide a drug deliverysystem comprising a pharmaceutical carrier that is a dispensablecomposition, that is innocuous, and when upon its displacement from thedelivery system substantially avoids mammalian tissue irritation andinteraction with mammalian protein tissue.

Another object of the present invention is to provide a delivery systemcomprising an inner capsule, which capsule houses at least one of ahydrophilic or a hydrophobic pharmaceutically acceptable carriercomprising insoluble to soluble drugs, and which carrier when thedelivery system i in operation is pushed substantially intact andsubstantially unchanged from the delivery system and changes itsphysical form on displacement from the delivery system in theenvironment of use.

Another object of the invention is to provide a drug delivery device fordispensing a drug to a ruminant, which delivery system comprises aninner lumen containing a nonmeltable and nonaqueous thermoplasticcomposition, a space occupying member, and a density member, and whichcomposition comprises a soluble to insoluble beneficial agent that canbe dispensed by the thermoplastic composition after said thermoplasticcomposition exits the delivery device.

Other objects, features and advantages of the invention will be moreapparent to those skilled in the dispensing art from the followingdetailed description of the specification, taken in conjunction with thedrawings and the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawing figures, which are not drawn to scale, but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows:

FIG. 1 is a view of a dispenser designed and manufactured for orallyadministering a beneficial agent to a warm-blooded animal;

FIG. 2 is an opened view of the dispenser of FIG. 1 through the verticallength of the dispenser for illustrating the structure of the dispenser,wherein the dispenser comprises an internal lumen housing apharmaceutically acceptable carrier that does not melt at thetemperature of an animal body, and which carrier comprises a continuousbody member extending through a major length of the lumen, and a spaceoccupying member for pushing the continuous carrier from the lumen;

FIG. 3 is an opened view of the dispenser of FIG. 1 taken in conjunctionwith FIG. 2, wherein FIG. 3 depicts the dispenser in operation with thecarrier formed of a composition that is thermally stable at thetemperature of an animal environment of use being urged from the lumenas the space occuying member consumer space in the lumen andconcomitantly urges the continuous carrier from the lumen of thedispenser;

FIG. 4 is an opened view taken with FIG. 3 depicting a semipermeablewall that surrounds that lumen with the dispenser in operation whereinthe thenmally stable carrier severs as it leaves the lumen and entersthe environment of use from the main body portion of the carrier stillcontained within the lumen of the dispenser;

FIG. 5 is an opened view of the dispenser depicting a different internalstructural configuration comprising a nonmeltable carrier, a volumeconsuming member, and a dense member for keeping the dispenser in therumen of an animal;

FIG. 6 is an opened view of the dispenser illustrating another internalstructural arrangement wherein the lumen comprises a carrier that isnonmeltable at animal temperatures, a density member for keeping thedispenser in an environment of use and positioned next to the carrier,and means for occupying space in the lumen for pushing the carrierthrough the mouth of the dispenser.

FIG. 7 is an opened view of the dispenser through the vertical length ofthe dispenser for illustrating the internal structure of the dispensercomprising an inside wall, an outside wall a carrier that maintains itsphysical and chemical integrity inside the dispenser, and means foroccupying space in the lumen for urging the carrier from the dispenser;

FIG. 8 is an opened view of the dispenser taken in conjunction with FIG.7, wherein the dispenser additionally contains a density member forkeeping the dispenser in the rumen of an animal;

FIG. 9 is an opened view of the dispenser illustrating a differentarrangement of the means for expanding and occupying space, and themeans for keeping the dispenser in the rumen of an animal over time;

FIG. 10 is a cross-section of a laminate provided by the inventioncomprising an erodible in direct contact with a lamina comprising meansfor keeping a dispenser in the rumen of a ruminant;

FIG. 11 is a cross-section through a laminate provided by the inventioncomprising an erodible lamina adjacent to a lamina comprising a memberselected from the group consisting of an osmopolymer and an osmagent;

FIG. 12 is a cross-section through a laminate provided by the inventioncomprising an erodible lamina in laminar arrangement with a laminacomprising means for producing a gas;

FIG. 13 depicts the imbibition pressure measured for various osmoticdriving members;

FIG. 14 depicts the volume per unit time for a number of compositions;

FIG. 15 depicts the release rate in mg/hr for various osmotic drivingmember;

FIG. 16 depicts the volume per unit time plotted against hydration H forvarious osmotic driving members using a carboxyvinyl polymer; and,

FIG. 17 depicts the volume per unit time plotted against hydration H forvarious osmotic driving members using a poly(oxyethylene) plus sodiumchloride osmotic driving composition.

FIG. 18 depicts the release rate per unit time for a driving compositioncomprising Carbopol®, a carboxyvinyl polymer, and sodium chloride; and,

FIGS. 19 to 24 depict the release rate and the cumulative amountreleased for a series of dispensers provided by the invention.

In the drawing figures ani in the specification, like parts in relatedfigures are identified by like parts. The terms appearing earlier in thespecification and in the description of the drawings, as well asembodiments thereof, are further detailed elsewhere in the disclosure.

DETAILED DESCRIPTION OF THE DRAWING FIGURES

Turning now to the drawing figures in detail, which are examples of newand useful dispensers for dispensing a beneficial agent, and whichexamples are not to be construed as limiting, one example of a dispenseris depicted in FIG. 1, identified by the numeral 10. In FIG. 1,dispenser 10 comprises a body 11 that surrounds and defines and internallumen, not seen in FIG. 1. Body 11 is formed of a wall 12 that definedand surrounds a wide-mouth opening 13 for delivering the contents ofdispenser 10 to an environment of use.

FIG. 2 is an opened view of dispenser 10 for illustrating the structureof the dispenser. Dispenser 10 of FIG. 2 comprises, body 11, wall 12 andmouth 13. Wall 12 surrounds an internal lumen 14. In a presentlypreferred embodiment wall 12 comprises in whole, or at least in part, asemipermeable wall forming composition that is substantially permeableto the passage of an external fluid and it is substantially impermeableto the passage of a beneficial agent other ingredients contained indispenser 10. In another embodiment, wall 12 can comprise asemipermeable composition, and in part wall 12 can comprise a differentcomposition. Wall 12 is non-toxic and it maintains its physical andchemical integrity, that is wall 12 does not erode during the dispensinglife of dispenser 10.

Wall 12 surrounds and defines an internal lumen 14. Lumen 14 containscarrier means 15 comprising beneficial agent 16, represented by dots 16.Lumen 14 also contains a driving means 17 that is layered and in contactwith carrier means 15. Both carrier means 15 and driving means 17 have ashape that corresponds to the internal shape of lumen 14. A passageway13, also identified for the purpose of this invention as a mouth,connects the outside of dispenser 10 with lumen 14. A passageway 13 thatis a wide-mouth opening in wall 12, which opening 13 comprises across-section that is substantially equal to the internalcross-sectional dimensions of lumen 14. In an optional embodiment, notshown, wall 12 at opening 13 can curve slightly inward for assisting ingoverning the movement of carrier means 15 from lumen 14.

FIG. 3 depicts dispenser 10 in operation in a biological fluidenvironment of use. Dispenser 10 in FIG. 3 comprises body 11, wall 12,mouth 13, lumen 14, pharmaceutically acceptable carrier means 15,beneficial agent 16 in pharmaceutically acceptable carrier means 15, andspace consuming means 17. Pharmaceutically acceptable carrier means 15keeps its integrity inside lumen 14. That is, carrier means 15 isnonmeltable at the temperature of use, it does not erode in the lumen,and it does not disintegrate, dissolve, decompose, or hydrolyze whilecarrier 15 is inside lumen 14. Space consuming member 17, in operationinside lumen 14, absorbs and or imbibes aqueous fluid through wall 12,thereby causing space consuming means 17 to continuously occupyadditional space in lumen 14. This occupying of space by means 17 causesmeans 17 to apply pressure against carrier 15 and urge it through mouth13. Carrier 15 as it enters the environment of use atcarrier-environment interface 18.

FIG. 4 depicts carrier 15 releasing beneficial agent 16 into theenvironment of use at interface 18. Carrier 15, in the presence of anaqueous-type biological fluid in the environment of use, releasesbeneficial agent 16 at a controlled rate by the process of erosion,leaching, osmotic bursting, or diffusion. Carrier 15, in the environmentbioerodes, disintegrates, dissolves or hydrolyzes as it enters theenvironment, thereby continuously presenting a new surface of carrier 15with its beneficial agent 16 to the environment. Dispenser 17 deliversbeneficial agent 16 at a controlled rate by the combined operations ofcarrier 15 releasing agent 16 and means 17 consuming space in lumen 14over time.

FIG. 5 illustrates dispenser 10 comprising in lumen 14 a dense member 19or densifier that is an important component of dispenser 10 for keepingdispenser 10 in the rumen of an animal over a prolonged period of time.In FIG. 5, lumen 14 houses pharmaceutical carrier means 15 in layeredcontact with a surface of space consuming means 17, which latter meansis in contact with densifier 19.

FIG. 6 illustrates another embodiment of dispenser 10 provided by thesubject invention. In FIG. 6, dispenser 10 is seen in opened view withlumen 14 housing pharmaceutically acceptable carrier means 15 in contactwith densifier 19. Densifier 19 is in contact with volume consumingmeans 17. In this embodiment, volume consuming means 17 is positioneddistant from mouth 13. The presence of densifier 19 in dispenser 10adapts dispenser 10 for use in a rumen. A rumen-retentive dispenser 10can be manufactured in a variety of sizes and shapes for administering abeneficial agent 16 to a ruminant animal. One presently preferred shapeis an elongated or lengthened shape such as a cylinder-like shape, or acapsule like shape with a wide mouth. For example, for use with sheep,dispenser 10 can embrace an elongated shape and have a diameter of about0.5 inches to 1 inch (1.3 cm to 2.5 cm), and a length of about 0.5inches to 4 inches (1.3 cm to 10 cm). For use with cattle, dispensersystem 10 comprises a diameter of about 0.5 inches to 1.5 inches (1.3 cmto 3.8 cm), and a length of about 1 inch to 6 inches (2.5 cm to 15 cm).

FIG. 7 is an opened view of another embodiment of dispenser 10 providedby the invention. In FIG. 7, dispenser 10 comprises wall 12 thatsurround internal wide-mouthed capsule 20. In one presently preferredembodiment comprising internal opened-mouth capsule 20, capsule 20surrounds lumen 14. Lumen 14 contains a nonthermo-responsive carrier 15containing beneficial agent 16. Lumen 14 further contains spaceconsuming means 17 that is in layered contact with a contacting surfaceof carrier means 15. In lumen 14, both carrier means 15 and spaceconsuming means 17 have a shape that corresponds to the internal shapeof lumen 14.

FIG. 8 is an opened view of another embodiment of a dispenser 10provided by the invention. In FIG. 8, dispenser 10 comprises an exteriorwall 12 that surrounds interior wall 20. Exterior wall 12 and interiorwall 20, in this manufacture jointly define internal space 14. Internalspace 14 contains pharmaceutical carrier means 15 having a beneficialagent 16 dispensed or dissolved therein, a density member 19 in contactwith carrier means 17 and a space consuming means 17 in contact with thedensity member 19. In this manufacture, space consuming means 17 isdistant from carrier means 15. In space or lumen 14, carrier means 15,density member 19 and space consuming means 17 all embrace a shape thatcorresponds to the internal shape of space 14.

FIG. 9 is an opened view of another manufacture of dispenser 1 providedby the subject invention. In FIG. 9, space consuming member 17 is incontact with the pharmaceutical carrier 15 and density member 19 isdistant from pharmaceutical carrier 15. In a presently preferredembodiment, as space consuming member 17 fills and takes up space inlumen 14, it maintains an immiscible boundary at the interface definedby means 15 and means 17.

FIG. 10 is an opened view of a bilaminate provided by the invention. Thelaminate corresponds to the internal arrangement depicted for dispenser10 depicted in FIG. 6. In FIG. 10, the lamina comprises an erodiblepolymeric lamina 15 containing beneficial agent 16, which lamina 15 isin laminar arrangement with lamina 19 comprising means for keepingdispenser 10 in a fluid environment of use.

FIG. 11 is a cross-section of a laminate comprising an erodible lamina15 containing a beneficial agent 16, which lamina 15 is in contact witha lamina 17 that consumes space inside dispenser 10.

FIG. 12 is a cross-section through a laminate comprising an erodiblelamina 15 containing a beneficial agent 16, which lamina 15 is incontact with a lamina 17 that comprises means for consuming space inlumen 14 of dispenser 10.

While FIGS. 1 through 9 are illustrative of various dispensers that canbe made according to the invention, it is to be understood thesedispensers are not to be construed as limiting, as the dispensers cantake a wide variety of shapes, sizes and forms adapted for delivering abeneficial agent to different fluid environments of use. For example,the dispenser includes implant, artificial gland, intrauterine, vagina,anal-rectal dispensers and the like. Dispenser 10 can be used inveterinary clinics, farms, zoos, laboratories, on the range, in feedlots, in hospitals, birth clinics, and other environments of use.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of this invention it has now been foundthat dispenser 10 can be manufactured with a lumen that houses incooperative relationship in lumen 14, carrier means 15, beneficial agent16, space consuming means 17 and in other optional embodiments densitymember 19. The dispenser 10 is formed by wall 12 comprising acomposition that does not adversely affect the carrier, the beneficialagent, the space consuming means, the density means, and otheringredients such as an osmagent, a gas generating couple, and the likethat can be housed in dispenser 10. Wall 12, is permeable in at least apart to the passage of an external fluid such as water and biologicalfluids, and it is substantially impermeable to the passage of beneficialagents, osmagents, osmopolymers, and the like. The wall comprises amaterial that does not adversely affect an animal, or host, or thecomponents comprising the device, and the selectively semipermeablematerials used for forming the wall are non-erodible and they areinsoluble in fluids. Typical selectively semipermeable materials forforming the wall are in one embodiment cellulose esters, celluloseethers and cellulose ester-ethers. These cellulosic polymers have adegree of substitution, D.S., on the anhydroglucose unit, from greaterthan 0 up to 3 inclusive. By degree of substitution is meant the averagenumber of hydroxyl groups originally present on the anhydroglucose unitcomprising the cellulose polymer that are replaced by a substitutinggroup. Representative compositions include a member selected from thegroup consisting of cellulose acylate, cellulose diacetate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di- and tricellulose alkanylates, mono-, di- andtricellulose aroylates, and the like. Exemplary polymers includecellulose acetate having a D.S. up to 1 and an acetyl content up to 21%;cellulose acetate having an acetyl content of 32 to 39.8%; celluloseacetate having a D.S. of 1 to 2 and an acetyl content of 21 to 35%;cellulose acetate having a D.S. of 2 to 3 and an acetyl content of 35 to44.8%, and the like. More specific cellulosic polymers include cellulosepropionate having a D.S. of 1.8 and a propyl content 39.2 to 45% and ahydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate having aD.S. of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29%,a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%;cellulose triacylates having a D.S. of 2.9 to 3 such as cellulosetrivalerate, cellulose trilaurate, cellulose tripalmitate, cellulosetrisuccinate, and cellulose trioctanoate; cellulose diacylates having aD.S. of 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate,cellulose dioctanoate, cellulose dipentanoate, co-esters of cellulosesuch as cellulose acetate butyrate and cellulose acetate propionate, andthe like.

Additional polymers include ethyl cellulose of various degree ofetherification with ethoxy content of from 40% to 55%, acetaldehydedimethyl cellulose acetate, cellulose acetate ethyl carbamate, celluloseacetate methyl carbamate, cellulose acetate dimethyl aminoacetate,semipermeable polyamides; semipermeable polyurethanes; semipermeablesulfonated polystyrenes; semipermeable cross-linked selective polymersformed by the coprecipitation of a polyanion and a polycation asdisclosed in U.S. Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006,and 3,546,142; semipermeable polymers as disclosed by Loeb andSourirajan in U.S. Pat. No. 3,133,132; semipermeable lightly cross-linedpolystyrene derivatives; semipermeable crosslinked poly(sodium styrenesulfonate); semipermeable cross-linked poly(vinylbenzyltrimethylammonium chloride); semipermeable polymers exhibiting a fluidpermeability of 2.5×10⁻¹¹ to 2.5×10⁻⁴ (cm² /hr. atm) expressed peratmosphere of hydrostatic or osmotic pressure or imbibition pressuredifference across the semipermeable wall. The polymers are known to theart in U.S. Pat. Nos. 3,845,770; 3,916,899, and 4,160,020, and inHandbook of Common Polymers by Scott, J. R. and Roff, W. J., 1971,published by CRC Press, Cleveland, Ohio.

Further in accordance with the practice of this invention, it has nowbeen found that internal wall 20 of dispenser 10 can be made as acapsule member. The capsule member generally is tubular shaped and ithas a mouth at one end, and at the end distant therefrom it is closed ina hemispherical or dome shaped end. The capsule member serves as ahollow body having a wall 20 that surrounds and defines an interiorcompartment 14 provided with an opening 13 for establishingcommunication with the exterior of the capsule and for filling thecapsule.

In one embodiment, a capsule is made by dipping a mandrel, such as astainless-steel mandrel, into a batch containing a solution of a capsulewall forming material to coat the mandrel with the material. Then, themandrel is withdrawn, cooled, and dried in a current of air. The capsuleis stripped from the mandrel and trimmed to yield a capsule with aninternal lumen. The materials used for forming the capsule are thecommercially available materials including gelatin, gelatin having aviscosity of 15 to 30 millipoises and a bloom strength up to 150 grams;gelatin having a bloom value of 160 to 250; a composition gelatin,glycerine water and titanium dioxide; a comprising gelatin, erythrosin,iron oxide and titanium dioxide; a composition comprising gelatin,glycerine, sorbitol, potassium sorbate and titanium dioxide; acomposition comprising gelatin, acacia, glycerin and water; watersoluble polymers that permit the transport of water therethrough and canbe made into capsules, and the like.

Wall 12 also can comprise a flux regulating agent. The flux regulatingagent is a compound added to assist in regulating the fluid permeabilityor flux through the wall 12. The flux regulating agent can be a fluxenhancing agent or a flux decreasing agent. The agent can be preselectedto increase or decrease the liquid flux. Agents that produce a markedincrease in permeability to fluid such as water, are often essentiallyhydrophilic, while those that produce a marked decrease to fluids suchas water, are essentially hydrophobic. The amount of regulator in thewall when incorporated therein generally is from about 0.01% to 20% byweight or more. The flux regulator agents in one embodiment thatincrease flux include polyhydric alcohols, polyalkylene glycols,polyalkylenediols, polyesters of alkylene glycols, and the like. Typicalflux enhancers include polyethylene glycol 300, 400, 600, 1500, 4000,6000 and the like; low molecular weight glycols such as polypropyleneglycol, polybutylene glycol and polyamylene glycol: thepolyalkylenediols such as poly(1,3-propanediol), poly(1,4-butanediol),poly(1,6-hexanediol), and the like; aliphatic diols such as 1,3-butyleneglycol, 1,4-pentamethylene glycol, 1,4-hexamethylene glycol, and thelike., alkylene triols such as glycerine, 1,2,3,-butanetriol,1,2,4-hexanetriol, 1,3,6-hexanetriol and the like; ester such asethylene glycol dipropionate, ethylene glycol butyrate, butylene glycoldipropionate, glycerol acetate esters, and the like. Representative fluxdecreasing agents include phthalates substituted with an alkyl, andalkoxy or with both an alkyl and alkoxy group such as diethyl phthalate,dimethoxyethyl phthalate, dimethyl phthalate, and [di(2-ethyl-hexyl)phthalate], aryl phthalates such as triphenyl phthalate, and butylbenzyl phthalate; insoluble salts such as calcium sulphate, bariumsulphate, calcium phosphate, and the like; insoluble oxides such astitanium oxide; polymers in powder, granule and like form such aspolystyrene, polymethylmethacrylate, polycarbonate, and polysulfone;esters such as citric acid esters esterfied with long chain alkylgroups; inert and substantially water impermeable fillers; resinscompatible with cellulose based wall forming materials, and the like.

Other materials that can be used to form the wall 12 for impartingflexibility and elongation properties to the wall, for making wall 12less-to-nonbrittle and to render tear strength, include phthalateplasticizers such as dibenzyl phthalate, dihexyl phthalate, butyl octylphthalate, straight chain phthalates of six to eleven carbons,di-isononyl phthalate, di-isodecll phthalate, and the like. Theplasticizers include nonphthalates such as triacetin, dioctyl azelate,epoxidized tallate, tri-isoctyl trimellitate, tri-isononyl trimellitate,sucrose acetate isobutyrate, epoxidized soybean oil, and the like. Theamount of plasticizer in a wall when incorporate therein is about 0.01%to 20% by weight, or higher.

Representative of means for manufacturing space consuming means 17 forurging pharmaceutically carrier means 15 from lumen 14 through mouth 13are at least one of a member selected from the group consisting of anosmopolymer, an osmagent and a gas generating couple. Exemplary of anosmopolymer that can be used for the present purpose is a hydrogel. Thehydrogel in the dispenser comprises a shape that corresponds to theinternal shape of lumen 14. The hydrogel composition is noncross-linkedor optionally cross-linked and it possesses osmotic properties such asthe ability to imbibe an exterior fluid through semipermeable wall 12,and exhibit an osmotic pressure gradient across semipermeable wall 12against a fluid outside dispenser system 10. The materials used forforming the space consuming member that are swellable and expandable,are polymeric materials neat, and polymeric materials blended withosmotic agents that interact with water or biological fluid, absorb thefluid and swell or expand to an equilibrium state. The polymer exhibitsthe ability to retain a significant fraction of imbibed fluid in thepolymer molecular structure. The polymers in a preferred embodiment aregel polymers that can swell or expand to a very high degree, usuallyexhibiting a 2 to 50 fold volume increase. The swellable, hydrophilicpolymers, also know as osmopolymers can be noncross-linked or lightlycross-linked. The cross-links can be covalent or ionic bonds with thepolymer possessing the ability to swell in the presence of fluid, andwhen cross-linked it will not be dissolved in the fluid. The polymer canbe of plant, animal or synthetic origin. Polymeric materials useful forthe present purpose include poly(hydroxyalkyl methacrylate) having amolecular weight of from 5,000 to 5,000,000; poly(vinylpyrrolidone)having a molecular weight of from 10,000 to 360,000, anionic andcationic hydrogels; poly(electrolyte) complexes; poly(vinyl alcohol)having a low acetate residual; a swellable mixture of agar andcarboxymethyl cellulose; a swellable composition comprising methylcellulose mixed with a sparingly cross-linked agar; polyethers having amolecular weight of 10,000 to 6 million; a water-swellable copolymerproduced by a dispersion of finely divided copolymer of maleic anhydridewith styrene, ethylene, propylene, or isobutylene; water swellablepolymer of N-vinyl lactams; and the like.

Other gelable, flid imbibing and retaining polymers useful such forforming the hydrophilic, expandable push member include pectin having amolecular weight ranging from 30,000 to 300,000; polysaccharides such asagar, acacia, karaya, tragacanth, algins and guar; Carbopol®, an acrylicacid polymer, a carboxyvinyl polymer, sometimes referred to ascarboxypolymethylene, a polymer of acrylic acid crosslinked with apolyallyl ether of succrose, as described in U. S. Pat. Nos. 2,798,053and 2,909,462 and available as Carbopols® 934, 940 and 941, and its saltderivatives; polyacrylamides; water-swellable indene maleic anhydridepolymers; Good-rite® polyacrylic acid having a molecular weight of80,000 to 200,000; Polyox® polyethylene oxide polymers having amolecular weight of 100,000 to 5,000,000; starch graft copolymers;Aqua-Keep® acrylate polymers with water absorbability of about 400 timesits original weight; diesters of polyglucan; a mixture of cross-linkedpolyvinyl alcohol and poly(N-vinyl-2-pyrrolidone); zein available asprolamine; poly(ethylene glycol) having a molecular weight of 4,000 to100,000, and the like. In a preferred embodiment, the expandable memberis formed from polymers and polymeric compositions that arethermoformable. Representative polymers possessing hydrophilicproperties are known in U.S. Pat. Nos. 3,865,108; 4,002,173; 4,207,893;4,327,725, and in Handbook of Common Polymers, by Scott and Roff,published by Cleveland Rubber Company, Cleveland, Ohio.

The osmagent that can be used for the purpose of providing spaceconsuming means 17 comprise inorganic and organic compounds that exhibitan osmotic pressure gradient against an external fluid acrosssemipermeable wall 12. Osmagents are also known as osmotically effectivecompounds and as osmotically effective solutes. The osmagent imbibesfluid from the outside of dispenser 10 into lumen 14 causing it toproduce a solution or a suspension that continuously occupies more spacein lumen 14. As more fluid is imbibed into lumen 14, it exerts apressure against pharmaceutically acceptable carrier 15 pushing it fromdispenser 10. Osmotically effective compounds useful for the presentpurpose include inorganic and organic salts, polysaccharides,carbohydrates, and the like. Representative solutes include magnesiumsulfate, magnesium chloride, sodium chloride, potassium chloride,lithium chloride, potassium sulfate, sodium carbonate, sodium sulfate,lithium sulfate, sodium sulfate, potassium acid phosphate, calciumlactate, tartaric acid, lactose, fructose, mannitol, sorbitol, andmixtures thereof. The osmotically active compound is initially presentin lumen 14 in excess and it can be in particle, crystal, pellet, powderor granule form. The osmotic pressure of an osmotic compound can bemeasured with a commercially available osmometer identified as VaporPressure Osmometer, Model 2B, available from Hewlett-Packard, Avondale,Penna. The osmotic pressure in atmospheres of osmagents suitable forthis invention will be greater than zero atm, generally from zero atm upto 500 atm, or higher.

The osmotically effective compound that can be blended homogeneously orheterogeneously with the swellable polymer, to form a push member 17,are the osmotically effective solutes that are soluble in fluid, imbibedinto the swellable polymer, and exhibit an osmotic pressure gradientacross the semipermeable wall against an exterior fluid. Osmoticallyeffective osmagents useful for the present purpose include magnesiumsulfate, magnesium chloride, sodium chloride, lithium chloride,potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol,succrose, glucose, and the like. The osmotic pressure in atmospheres,atm, of the osmagents suitable for the invention will be greater thanzero atm, generally from greater than zero atm up to 500 atm, or higher.The swellable, expandable polymer, in addition to providing a drivingsource 17 for urging carrier 15 containing beneficial agent 16 fromdispenser 10, further serves to function as a supporting matrix for anosmotically effective solute. The osmotic solute can be homogeneously orheterogeneously blended with the polymer to yield the desiredexpandable, member 17. The composition in a presently preferredembodiment comprises at least one polymer and at least one osmoticsolute. Generally, a composition will comprise about 20% to 90% byweight of polymer and 80% to 10% by weight of osmotic solute, with apresently preferred composition comprising 35% to 75% by weight ofpolymer and 65% to 25% by weight of osmotic solute.

The gas generating couple operable as space occupying means 17 is, in apresently preferred embodiment, an effervescent couple or composition.The gas generating couple comprises at least one preferably solid acidicmaterial and preferably solid basic material that dissolve and react inaqueous fluid that enters the dispenser to produce carbon dioxide. Thegaseous generation of carbon dioxide leads to the volume displacement ofcarrier 15 containing beneficial agent 17 from dispenser 10. The gasgenerating couple can be present in powder, crystalline, granular,compressed forms, and the like. The acidic or acids that can be usedinclude organic acids such as malic, fumaric, tartaric, itaconic,maleic, citric, adipic, succinic and mesaconic, and the correspondinganhydride such as itaconic anhydride, and citriconic anhydride. Alsoinorganic acids such as sulfamic or phosphoric, and the like can be usedfor gas generation. Acid salts such as th salts of organic foods can beused including monosodium citrate, potassium acid tartrate, andpotassium bitartrate. The basic compounds include metal carbonate andbicarbonate salts such as alkali metal carbonates and bicarbonates, oralkaline earth carbonates and bicarbonates. Exemplary materials includethe alkali metals lithium, sodium, and potassium carbonate andbicarbonate, and the alkaline earth compounds magnesium and calciumcarbonate or bicarbonate. Also useful are ammonium carbonate, ammoniumbicarbonate and ammonium sesquecarbonate. The combination of certain ofthese acids and bases results in a more rapid gas production oreffervescence when contacted by water. In particular, either citric acidor a mixture of citric acid and tartaric acid and sodium bicarbonategive a rapid gaseous reaction that can be used for urging carrier 17from dispenser 10. It will be understood the amount of acidic and basicmaterials in a couple can vary over a wide range to satisfy the amountof gas generation need to urge carrier 17 from dispenser 10. Theessentially anhydrous or dry couple is preferably substantiallystoichiometrically balanced to produce a combination that generatescarbon dioxide. Also, the acid and base materials can be used in anyconvenient proportion between 1 to 200 parts and 200 to 1 part on aweight basis to produce the desired results. In addition, the gasgenerating material can be a substance that generates gas on contactwith water such as calcium carbide or carbure.

Pharmaceutically acceptable carrier means 15 in a presently preferredembodiment maintains its physical and chemical integrity inside lumen 14of dispenser 10. The phrase "maintains its physical and chemicalintegrity inside lumen 14", used for the purpose of this invention,denotes a carrier formulation that does not substantially undergo changein lumen 14 of dispenser 10. That is, carrier formulation 15 does nothydrolyze, erode, disintegrate or dissolve in lumen 14 during operationof dispenser 10. The expression "nonmeltable", as used for the purposeof this invention means carrier 15 substantially does not melt insidelumen 14 of dispenser 10. That is, carrier 15 inside lumen 14substantially does not change from a solid to a liquid state. Carrierformulation 15, on its delivery from dispenser 10 can, in a fluidbiological environment of use, such as the gastrointestinal tract of awarm-blooded animal undergo hydrolysis in the acidic or basic pH of thetract, it can undergo surface erosion, disintegrate, dissolve, behydrolyzed by enzymes, digested by bacteria or fungi, and the like.

Exemplary of carrier formulation means 15 generically include a memberselected from the group consisting of a polyester, polylactide,polyacetal, polyorthoester, polyorthocarbonate, and the like.

Representative of more specific carrier formulations 15 include a memberselected from the group consisting of polyglycolic acid exhibiting a Tmof 230° C. wherein Tm is the melting point, polydiglycolide having a Tmof 230° C., polylactic acid having a Tm of 180° C., polydilactide havinga Tm of 180° C., polydimethylglycolic acid with a Tm of 240° C.,polycaprolactone having a Tm of 63° C., polyalkylene adipate wherein thealkylene group comprises 10 carbons having a Tm of 77° C.,polylactide-co-glycolide, and the like.

Representative of additional compositions for forming carrier means 15comprise polyanhydrides, polyanhydride polymers of sebacic and azelaicacid, hydrophobic polycarbolyic acids having one ionizable carboxylichydrogen for each 8 to 22 total carbon atoms, bioerodible polymers thatinnocuously disintegrate or breakdown as a unit structure on release bydispenser 10 such as a hydrophobic polycarboxylic acid having arepeating backbone unit of 8 to 22 carbon atoms for each pendantcarboxylic hydrogen; a bioerodible polyvalent ion cross-linkedpolyelectrolyte with a polyvalent ion selected from the group consistingof aluminum, barium, cadmium, calcium, copper, iron and zinc with thepolyelectrolyte selected from the group consisting of carrageenan,pectic acid, pectinic acid and the like; a polyester of the formula[-0-W-CO]y wherein W is an alkylene of 1 to 4 carbons and y is a wholenumber to provide a polymer having a molecular weight of 4,000 to100,000; a polyorthoester selected from the group consisting ofpoly(2,2-dioxo-trans-1,4-cyclohexane dimethylene tetrahydrofuran),poly(2,2-dioxo-1,6-hexamethylene tetrahydrofuran), poly(1,4-cyclohexanedicarbinyl-2,2-dioxtetrahydrofuran), poly(2,2-dioxohexamethylene-1,3-dioxolane),poly(2,2-dioxa-trans-2-methyl-cylclohexane-1,4-diethylene-2-pyrrolidone),poly(2,2-dioxa-us, trans-,4-cyclohexane-dimethylene-2-thiocane), and thelike. Representative of additional compositions for forming carriermeans 15 include polyamino acid, polypeptide, polyglutamate,polyglutamic acid, polylysine, and the like.

Representative of additional polymeric materials for providing carriermeans 15 are a hydrophilic polymer selected from the group, consistingof a poly(alginate), poly(carrageenan), poly(guar gum), poly(gum agar),poly(gum arabic), poly(gum ghatti) poly(gum paraya), poly(gumtragacanth), poly(tamarid gum), poly(xanthan gum) and the like. Thehydrophilic polymeric material, when used for carrier means 15,comprises a different polymeric composition when a hydrophilic polymericmaterial is used for space consuming member 17, or when carrier means 17and space consuming means 17 are in contact with each other.

Carrier means 15, in additional operative embodiments, can bemanufactured by (1) compressing water insoluble materials into a shapethat corresponds to the internal shape of lumen 14. For example, carriermeans 15 can comprise a tableted, an elongated stick-like shape, or thelike. Carrier means 15, in its additional operative embodiments,maintains its integrity in lumen 14, and on its exit from dispenser 10disintegrates, or the like, in the fluid environment of use. In thismanufacture, carrier means 15 can comprise polymerized particulatecomposition of matter comprising polyethylene, polypropylene, celluloseacetate, ethylcellulose, polysulfone, cellulose acetate butyrate,microcrystalline cellulose, and the like.

Carrier means 15, in another embodiment, can be manufactured from (2)substantially insoluble organic and inorganic substances. Carrier 15, inthis embodiment, keeps its shape in lumen 14 but loses its shape in anenvironment of use. Representative of insoluble organic and insolubleinorganic solids used for this purpose comprise a member selected fromthe group consisting essentially of calcium carbonate, calcium sulfate,diatomaceous earth, clay, silicon dioxide, pulverized glass, and thelike.

A carrier means 15, with operative properties can be manufactured, inone embodiment, with good properties for engaging in contacting relationwall 12 or wall 20, by compounding a member selected from group (1) witha member selected from group (2). For example, materials selected from(1) and (2) are mixed with each other and with a lubricant or an oil andthen with a small quantity of a member selected from the groupconsisting of a swellable polymer such as gelatin,hydroxypropylmethylcellulose, pectin, and the like, and with adisintegrating agent such as solks floc, and the like. The presence ofthe disintegration agent in carrier 15 on carrier 15's exposure to theenvironment of use results in the break up of the carrier into smallparts with a concurrent delivery of the beneficial agent 16 in theenvironment of use.

The expression active agent 16 as used herein, includes any beneficialagent, or beneficial compound, that can be delivered from the dispenserto produce a beneficial and useful result. The agent can be insoluble tovery soluble in the pharmaceutically acceptable carrier 15. The termactive agent includes algicide, antioxidant, air purifier, biocide,bactericide, catalyst, chemical reactant, disinfectant, fungicide,fermentation agent, fertility inhibitor, fertility promoter, germicide,plant growth promoter, plant growth inhibitor, preservative,rodenticide, sterilization agent, sex sterilant, and the like.

In the specification and the accompanying claims, the term beneficialagent also includes drug. The term "drug" includes any physiologicallyor pharmacologically active substance that produces a local or systemiceffect, in animals, including warm blooded mammals; humans and primates;avians., household, sport and farm animals; laboratory animals; fishes;reptiles and zoo animals. The term "physiologically", as used herein,denotes the administration of a drug to produce generally normal levelsand functions. The term "pharmacologically", denotes generallyvariations in response to the amount of drug administered to the host.See Stedman's Medical Dictionary, 1966, published by Williams andWilkins, Baltimore, Md.

The active drug that can be delivered includes inorganic and organiccompounds without limitation, including drugs that act on the peripheralnerves, adrenergic receptors, cholinergic receptors, nervous system,skeletal muscles, cardiovascular system, smooth muscles, bloodcirculatory system, synaptic sites, neuroeffector junctional sites,endocrine system, hormone systems, immunological system, reproductivesystem, skeletal system, autacoid systems, alimentary and excretorysystems, inhibitory of autocoid systems, alimentary and excretorysystems, inhibitory of autocoids and histamine systems. The active drugthat can be delivered for acting on these recipients includeanticonvulsants, analgesics, antiparkinsons, anti-inflammatories,calcium antagonists, anesthetics, antimicrobials, antimalarials,antiparasites, antihypertensives, antihistamines, antipyretics,alpha-adrenergic agnoist, alpha-blockers, biocides, bactericides,bronchial dilators, beta-adrenergic blocking drugs, contraceptives,cardiovascular drugs, calcium channel inhibitors, depressants,diagnostics, diuretics, electrolytes, hypnotics, hormonals,hyperglycemics, muscle contractants, muscle relaxants, opthalmics,psychic energizers, parasympathomimetics, sedatives, sympathomimetics,tranquilizers, urinary tract drugs, vaginal drugs, vitamins,nonsteroidal anti-inflammatory drugs, angiotensin converting enzymes,polypeptide drugs, and the like.

Exemplary drugs that are very soluble in water and can be delivered bythe dispenser of this invention include prochlorperazine edisylate,ferrous sulfate, aminocaproic acid, potassium chloride, mecamylaminehydrochloride, procainamide hydrochloride, amphetamine sulfate,benzphetamine hydrochloride, isoproteronol sulfate, methamphetaminehydrochloride, phenmetrazine hydrochloride, bethanechol chloride,methacholine chloride, pilocarpine hydrochloride, atropine sulfate,scopolamine bromide, isopropamide iodide, tridihexethyl chloride,phenformin hydrochloride, methylphenidate hydrochloride, cimetidinehydrochloride, theophylline cholinate, cephalexin hydrochloride, and thelike.

Exemplary drugs that are poorly soluble in water and that can bedelivered by the dispenser of this invention include diphenidol,meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine,thiethylperazine maleate, anisindone, diphenadione erythrityltetrantrate, digoxin, isoflurophate, acetazolamide, methazolamide,bendroflumethiazide, chlorpropamide, tolazamide, chlormadione acetate,phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetylsulfisoxazole, erythromycin, progestins, esterogenic, progestational,corticosteroids, hydrocortisone, dydrocortiocosterone acetate, cortisoneacetate, triamcinolone, methyltesterone, 17 beta-estradiol, ethinylestradiol, ethinyl estradiol 3-methyl ether, pednisolone, 17beta-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel,norethindrone, norethisterone, norethiederone, progesterone,norgesterone, norethynodrel, and the like.

Examples of other drugs that can be delivered by the dispenser includeaspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen,nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol,alprenolol, cimetidine, clonidine, imipramine, levodopa,chloropromazine, methyldopa, dihydroxyphenylalanine, pivaloyloxyethylester of alpha-methyldopa hydrochloride, theophylline, calciumgluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol,zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine,diltiazem, milrinone, captopril, madol, quanbenz, hydrochlorothiazide,ranitidine, flurbiprofen, fenbufen, fluprofen, tolmetin, alolofenac,mefenamic, flufenamic, difuninal, nimodipine, nitrendipine, nisoldipine,nicardipine, felodipine, lidoflazine, tiapamil, gallopamil amlodipine,mioflazine, lisinolpril, enalapril, captopril, ramipril, endlapriat,famotidine, nizatidine, sucralfate, etintidine, tertatolol, minoxidil,chlordiazepoxide, chlordiazepoxide hydrochloride, diazepan, amitriptylinhydrochloride, impramine hydrochloride, imipramine pamoate, and thelike. The beneficial drugs are known to the art in PhanmaceuticalSciences, 14th Ed., edited by Remington, (1979) published by MackPublishing Co. Easton, Pa.: The Drug, The Nurse, The Patient, IncludingCurrent Drug Handbook, by Falconer, et al, (1974-1976) published bySaunder Company, Philadelphia, Pa.; Medicinal Chemistry, 3rd Ed., Vol 1and 2, by Burger, published by Wiley-Interscience, New York; and inPhysicians' Desk Reference, 38 Ed., (1984) published by MedicalEconomics Co., Oradell, N.J.

The drug can be in various forms, such as uncharged molecules, molecularcomplexes, pharmacologically acceptable salts such as hydrochloride,hydrobromide, sulfate, laurate, palmitate, phosphate, nitrite, borate,acetate, maleate, tartrate, oleate and salicylate. For acidic drugs,salts of metals, amines or organic cations; for example, quarternaryammonium can be used. Derivatives of drugs such as ester, ethers andamides can be used. Also, a drug that is water insoluble can be used ina form that is water soluble derivative thereof to serve as a solute,and on its release from the device, is converted by enzymes, hydrolyzedby body pH or other metabolic processes to the original biologicallyactive form. The amount of beneficial agent in a dispenser generally isabout from 0.05 ng to 10 g or more, with individual dispensercontaining, for example, 25 ng, 1 mg, 5 mg, 10 mg, 25 mg, 125 mg, 250mg, 500 mg, 750 mg, 1.0 g, 1.2 g, 1.5 g, 4.5 g, 7.5 g, and the like, foradministering to a human.

The term beneficial agent as used herein also comprises medicines ordrugs, nutrients, vitamins, food supplements and other agents that areadministered to farm animals. The dispenser can house various amounts ofbeneficial agents for administering to a farm animal, usually from 75 ngto 50 g for farm animals, for example, 75 ng, 1 mg, 5 mg, 100 mg, 250mg, 500 mg, 750 mg, 1.5 mg, 2 g, 5 g, 10 g, 25 g, and the like. A singledispenser can be administered to a farm animal, for example to aruminant, or more than one dispenser can be administered to a ruminantduring a therapeutic program. Dispensers can be provided that have arate of release from 5 micrograms to 5 grams per day, or higher for afarm animal.

Representative of beneficial medicaments that can be dispensed to a farmanimal using the delivery system 10 of this invention includeanthelmintics such as benzimidazole, mebendazole, levamisole,albendazole, cambendazole, fenbendazole, parbendazole, oxfendazole,oxybendazole, thiabendazole, tichlorfon, praziquantel, thiophanate,morantel, morantel tartrate, pyrantel, pyrantel tartrate, methoprene,and the like; antiparasitic agents for the management of endoparasitesand ectoparasites, such as avermectin and ivermectin, as disclosed inU.S. Pat. Nos. 4,199,569 and 4,389,397 both assigned to Merck & Co., andin Science, Vol 221, pp 823-828, 1983, wherein said ivermectinantiparasitic drugs are disclosed as useful for aiding in controllingcommonly occurring infestations in farm animals, such as roundworms,lung worms and the like; and said ivermectin also being used for themanagement of insect infestations such as grub, lice, mange mite, mite,ticks, larve, flies such as larve warble fly, dung-breeding fly, larveand flies in the excreta of animals; and the like, with delivery systemadministering from 5 micrograms per kilogram per day (5 μg/kg/d), to 250milligrams per day (250 mg/kg/d), to cattle for establishing avermectin,including ivermectin, blood levels; antimicrobial agents such aschloretetracycline, oxytetracycline, tetracycline, streptomycin,dihydrostreptomycin, bacitracins, erythromycin, chlortetracycline,ampicillins, penicillins, cephalosporins, and the like; sulfa drugs suchas sulfamethazine, sulfathiazole, sulfonamides, and the like; macrolidessuch as erythromycin, spiramycin, tylosin and the like; nitrofurans;antibiotics; ionaphores such as lasalocid, salinomycin, virginamycin,ronnel and the like; growth-stimulants such as Monesin® sodium, andElfazepam®; defleaing agents such as dexamthazone and flumethazone;rumen fermentation manipulators; antibloat agents such asorgano-polysiloxanes; growth promoting agents; minerals; mineral saltsand trace elements formulations such as magnesium, copper, cobalt, iron,manganese, molybdenum, zinc, selenuim, copper oxide, copper sulfate,cobalt salt, copper salt, selenium salt, selenium disulfied, sodiumselenite, inorganic, organic compounds, cobalt oxide, and the like;hormone growth supplements such as stilbestrol; growth efficiencyfactor, beta-agonist such as denbuterol; vaccines such as bovinediarrhea vaccine; vitamins such as vitamin A, B-group, C, D, E, K andthe like; antienteritis agents such as furazolidone; nutritionalsupplements such as lysine, lysine monhydrochloride, methionine,mexhionine salts, amino acids, peptides, and the like; beneficial alphaagonists, and the like.

Pharmaceutically acceptable carrier means 15 on leaving lumen 14 ofdispenser 10 delivers a beneficial agent 16 to a gastrointestinal tractby rate controlled kinetics. For example the pharmaceutical carriermeans 15 can deliver a beneficial agent 16 as a rate controlled bydiffusion, by osmosis, by ommotic bursting, by solution leaching, bysolubilization by cross-link cleavage, by solubilization of carriermeans 15, by hydrolysis, by solubilization of carrier means 15 byionization of pendant groups, by solubilization of carrier means 15 byprotonation of pendant groups, by solubilization by backbone cleavage,by biodegradation, by bioerosion, by enzymatic action, by oxidation, byreduction, by proteolysis, by displacement, by dissolution, bydisintegration, and the like.

The density member 19, also referred to as densifier 19, used indispenser 10, is dense enough to retain dispenser 10 in therumenreticular sac of a ruminant. Density member 19 lets dispenser 10remain in the rumen over a prolonged period of time rather than lettingit pass into the alimentary tract and be eliminated therefrom. As system10 remains in the rumen, beneficial active agent 16 is delivered bysystem 10 at a controlled rate to the ruminant over time. Generally,dense member 19 will have a density of from about 0.8 to 8, or higher,with the density in a presently preferred embodiment exhibiting aspecific gravity of from 1.2 to 7.6. For the ruminants, cattle andsheep, it is presently preferred dense member 19 exhibit a density suchthat there is a resulting system density of about 3 gm/ml. Materialsthat have a density that can be used for forming dense member 19 includeiron, iron shot, iron shot coated with iron oxide, iron shot magnesiumalloy, steel, stainless steel, copper oxide, a mixture of cobalt oxideand iron powder, and the like. Dense member 19 in delivery system 10 canembrace different embodiments. For example, dense member 19 can bemachined or cast as a single, solid piece made of stainless steel havinga density of 7.6 gm/ml. The solid member is made having a curved shapethat corresponds to the internal shape of system 10. The solid membercan have an axially aligned bore that extends through the length of theunit member. In another embodiment, dense member 19 can compose aplurality of dense pellets or lamella. Density member 19 is describedabove consists of means having a specific gravity greater than the fluidenvironment of use for keeping dispenser 10 in the fluid environmentover time.

The semipermeable wall forming composition can be applied to theexterior surface of a dispenser alone or in laminar arrangement bymolding, air spraying, dipping or brushing with a semipermeable wallforming composition. Other and presently preferred techniques that canbe used for applying the semipermeable wall are the air suspensionprocedure and the pan coating procedures. The air procedure consists insuspending and tumbling the lumen forming components in a current of airand a semipermeable wall forming composition until the wall surroundsand coats the components. The procedure optionally can be repeated witha different semipermeable wall forming composition to form asemipermeable capsule laminated wall. The air suspension procedure isdescribed in U.S. Pat. No. 2,799,241; J. Am. Pharm. Assoc., Vol 48, pp451 to 459, 1979; and ibid, Vol 49, pp 82 to 84, 1960. Other standardmanufacturing procedures are described in Modern Plastics Encyclopedia,Vol 46, pp 62 to 70, 1969; and in Pharmaceutical Sciences, by Remington,14th Edition, pp 1626 to 1678, 1970 published by Mack Publishing Co.,Easton, Pa. In those manufactures wherein the wall is coated by airsuspension or by pan coating techniques, mouth 13 is formed in the wallby one of a number of techniques such as laser cutting, milling, sawing,drilling, and the like, wherein the device or the mouth-cutting tool isin motion or is stationary.

Exemplary solvents suitable for manufacturing the wall 12 include inertinorganic and organic solvents that do not adversely harm the materials,the capsule wall, the beneficial agent, the carrier composition, theexpandable member, the dense member, and the final dispenser. Thesolvents broadly include members selected from the group consisting ofaqueous solvents, alcohols, ketones, esters, ethers, aliphatichydrocarbons, halogenated solvents, cycloaliphatics, aromatics,heterocyclic solvents and mixtures thereof. Typical solvents includeacetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butylalcohol, methyl isobutyl ketone, methyl propyl ketone, n-hexane,n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethylacetate, methylene dichloride, ethylene dichloride, propylenedichloride, carbon tetrachloride, nitroethane, nitropropane,tetrachlorethane, ethyl ether, isopropyl ether, cyclohexane,cyclo-octane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran,diglyme, water, and mixtures thereof such as acetone and water, acetoneand methanol, acetone and ethyl alcohol, methylene dichloride andmethanol, and ethylene dichloride and methanol.

DESCRIPTION OF EXAMPLES OF THE INVENTION

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

EXAMPLE 1

The operation of a dispenser 10 manufactured according to the inventionis set forth in this example. The volume delivery rate of the drugformulation compartment 14 is equal to the volume rate of waterimbibition (dV/dt) into the osmotic agent formulation compartment 17expressed by equation (1) as follows: ##EQU1## where k is the waterpermeability of the semipermeable wall, h is the thickness of the wall,A is the wall surface exposed to the osmotic process, and Δπ is theosmotic pressure difference across the wall. The geometrical shapeconsidered here is as shown in FIG. 13, with flat bottom and cylindricalbody. The volume rate of water imbibition can be related to the totalsurface area for water transport A from the end and cylindrical sectionsfrom equations (2) and (3):

    A=πr.sup.2 +2 rl                                        (2)

where l is the height of the osmotic formulation. ##EQU2## where V isthe volume of osmotic formulation. The volume expansion of the osmoticdriving member equals

    V=V.sub.o +V.sub.H                                         (4)

where V_(o) and V_(H) are, respectively, the volumes of dry osmoticagent formulation and water imbibed. Alternatively, (4) can be written##EQU3## where ρ_(o) is the density of dry osmotic agent formulation,W_(o) and W_(H) are the weights of osmotic agent and water imbibed, andρ_(H) is the density of water.

Rearranging tenms within the equations, the following equation results:##EQU4## Therefore, the volume rate of water imbibition is expressed by:##EQU5## and the release rate of the drug from dispenser 10 becomes:##EQU6## where C_(d) is the concentration of drug in the carrier phase.

Equation (9) considered in conjunction with (8), allow for numerousdelivery rates and drug programs derived from system 10 geometry and theosmotic pressure Δπ programmed in the dispenser as a function of time.

For development of the example, Eq. (10) will be substituted in thesubsequent equations. ##EQU7##

Based on the composition of the carrier phase C_(d) system 10 geometryand osmotic properties of the driving chamber 17, simulations of therelease rate profile were calculated as shown in FIG. 14 for a givenwall composition and various values of M_(o) from 4 to 8 gram. Δπ givenas in equation (11) and in equation (12) based on experimental data arepresented herein.

    Δπ=π.sub.o for H<0.1                           (11)

    Δπ(H)=exp [A(Ln H).sup.2 +B 1nH+C] for 0.1<H<1    (12)

Substituting equation (12) and equation (13) in equation (1), equation14 results as follows: ##EQU8##

In addition, (15) holds for the volume of absorbed water V_(H) ##EQU9##

Since the volume of formulation displaced (16) is related to H by (15),##EQU10## it follows that (17) results ##EQU11##

The solution of this differential equation will result in H(t) which canbe substituted in (14) to yield the release rate. The solution toequation (17) was solved by numerical integration, resulting in thesimulations for the release rates given in FIG. 14. The numericalintegration of (17) is obtained from (18) as follows: ##EQU12## Thefinal value at shutdown for system 10 for H_(f) and t_(f) is given byequation (19): ##EQU13## Here ρ_(dc) and W_(dc) are the density andweight of the drug compartment 14. The function H(t) is obtained byfinding the time t_(i) associated with the hydration value H_(i). Thefinal value of H, H_(f) equation (19), can be reached after m equalsteps ΔH, such that (20) results, and also (21). ##EQU14## The timet_(i) associated with H_(i) is calculated from equation (22) wheref(H_(j)) is the average value of expression (17) between the start andend of the interval i: ##EQU15##

Here Δt_(i) is given by (23) ##EQU16## From (9), (15), (16) and (23), itfollows then that the delivery rate ##EQU17## as a function of time isgiven by (24). ##EQU18##

EXAMPLE 2

The delivery rate of dispenser 10 can be programmed by using the factorsas described in Example 1. In this example, a formulation comprising anosmagent is described with its effect on the release of an active agent.A formulation of osmagent comprises a blend of sodium carbopol 934 andsolium chloride in a 70:30 ratio. The osmotic pressure π at fourhydration values H was measured and as listed in Table 1, and can bedescribed as follows: ##EQU19##

                  TABLE 1                                                         ______________________________________                                        Osmotic Pressure of                                                           Carbopol (70)/NaCl(30) Formulation                                            π(atm)    Hydration (H)                                                    ______________________________________                                        400          0.25                                                             380          0.50                                                             340          0.75                                                             310          1.00                                                             ______________________________________                                    

EXAMPLE 3

Following the above described procedures, a dispenser 10 was made withthe parameters listed in Table 2. The dispenser comprises a wall 12having a total weight of 1.8 g and comprising 91% cellulose acetatebutyrate having an acetyl content of 38.1% and 9% polyethylene glycol400.

                  TABLE 2                                                         ______________________________________                                        Wall thickness:   h = 0.51 mm (20 mil)                                        Wall radius:      r = 0.93 mm                                                 Push tablet height:                                                                             L = 1.8 cm                                                  Mass of drug compartment:                                                                       W.sub.dc = 4.36 gr                                          Density of drug compartment:                                                                    ρ.sub.dc = 1.0                                          Density of push compartment:                                                                    l.sub.p = 1.4                                               Drug loading in carrier phase                                                                   C.sub.d = 0.06 gr/ml                                        Wall permeability k = 2.28 10.sup.-5 cc.mil/cm.sup.2 hr                       ______________________________________                                    

FIG. 15 shows the release rate from the dispenser comprising weights ofosmagnets from 4 to 8 grams.

Additional studies were performed to show the rate of release fromdispeser 10 with a series of osmagnets. The imbibition pressure of threecompositions were measured as a function of hydration and plotted inFIG. 13. In FIG. 13, the line with triangles denotes Polyox®coagulant(polyethylene oxide) with a molecular weight of about 5,000,000plus 29% sodium chloride, the line with squares denotes Polyox®coagulant with a molecular weight of 5,000,000; and the line withcircles denotes Carbopol® polymer, a carboxyvinyl polymer with amolecular weight of 100,000 and 29% sodium chloride. The data in FIG. 13can be described by the following equation (Y) wherein π(atm)=C X H^(N)and the constants C and N are given in Table 3.

                  TABLE 3                                                         ______________________________________                                        Composition                                                                   of Osmagent         C       N                                                 ______________________________________                                        Polyox Coagulant    96      -1.38                                             71% Carbopol + 29% NaCl                                                                           88      -0.51                                             71% Polyox + 29% NaCl                                                                             315     -0.54                                             ______________________________________                                    

Given the above osmotic pressures the volumetric delivery rates dV/dt,equation (14) Examples can calculated for a cylindrically shaped bolusby equation (14) as function of degree of hydration (H). The calculationshows that the release rate can be programmed by varying the diameter orradius of the system, the thickness of the layer of osmagent andselection of the osmagent. FIGS. 14, 16 and 17 show the volumetricdelivery rate normalized to the initial rate of H=0.1 as a function ofhydration (H) for various compositions of osmagent, diameter of thesystem, thickness and weight of the osmopolymer layer. The data indicatethat the volumetric rates can be decreasing or increasing as a functionof the degree of hydration.

EXAMPLE 4

In this example a dispenser was provided with the following properties:

1. Osmotic driving member: 71% polyoxyethylene mol. wt. 5,000,000 plus29% NaCl.

2. Wall composition: cellulose acetate butyrate with k=6.13×10⁻⁵cm.mil/hr.atm.

3. Weight of drug layer; 4.36 g.

4. Weight of drug in drug layer: 6%.

5. Dispenser's diameter: 1.86 cm.

6. Release rate for different weights of osmotic driving members, W_(o),between 4 to 8 g are plotted in FIG. 18.

EXAMPLE 5

A dispenser for the controlled delivery of ivermectin is made asfollows: first, 190 g of poly (2.2-dioxo-trans-1,4-cyclohexanedimethylene tetrahydrofuran) is heated in a laboratory Teflon® panequipped with a surface thermometric to about 150° C., and then 14 g isadded thereto and the two components blended into a homogeneouscomposition Next, the composition is molded into a cylindrical shape andcooled to room temperature. Next, the bioerodible composition is placedinto a wide mouth capsule previously charged at its closed bottom firstwith a 30 g stainless steel density member and then with an expandabledriving member. The driving member comprises 2 g of sodium chloride and5 g of sodium salt of polyacrylic acid available as Carbopol® 934Ppreviously pressed into a tablet. The tablet is formed using a 18.2 mmtableting tool and about 31/2 tons of compression force. The tabletcompresses a final shape that corresponds to the internal shape of theopening of the capsule. The expandable tablet has a surface in contactwith the pharmaceutical invermectin composition. Next, the capsule iscoated on its exterior surface up to its mouth by dipping it into wallforming composition. The wall forming composition comprises 1.8 g of 91%cellulose acetate butyrate and 9% polyethylene glycol 400. The wall isapplied from a 5% wt/wt solution of methylene chloride methanol 90:10v/v solvent system. The wall coated dispenser is dried at about 25° to30° C. for 24 hrs. The dispenser provided by this example deliversinvermectin to a rumen over a long period of time.

EXAMPLE 6

A dispenser is made according to the procedure set forth in Example 5,with the manufacturing conditions as set forth, except that in thisexample the pharmaceutically acceptable carrier comprises a condensationcopolymer of 3.9-bis(ethylidence)-2,4,8,10-tetraoxospiro[5.5] undecaneand 1,6-hexanediol. The copolymer can be prepared according to thesynthesis described in U.S. Pat. No. 4,304,767.

EXAMPLE 7

A dispenser is made according to the procedure set forth in Example 5,with the manufacturing conditions as set forth, except that in thisexample the pharmaceutically acceptable carrier comprises a condensationcopolymer of 3,9-bis(ethylidine)-2,4,8,10-tetraoxospiro[5.5] undecaneand the diol ethylene glycol. The copolymer can be prepared according tothe synthesis described in U.S. Pat. No. 4,304,767.

EXAMPLE 8

A dispenser is made according to the procedure set forth in Example 5,with the manufacturing conditions as set forth, except that in thisexample, the pharmaceutically acceptable carrier comprises a polymer ofpolyols and ketene acetals having a functionality of two or more asdisclosed in U.S. Pat. No. 4,304,767, and in J. Cont. Rel. Vol. 4, pp87-95, 1986. Excipients used to catalyze a controlled surface erosionprocess of the pharmaceutically acceptable carrier are disclosed in J.Cont. Rel. Vol. 1, pp 225-232, 1985.

EXAMPLE 9

A dispenser is made according to the procedure set forth in Example 5,with the manufacturing conditions as set forth, except that in thisexample, the pharmaceutically acceptable means comprises the hydrophobiccopolymer poly(2,2-dioxo-trans-1,4-cyclohexane-dimethylenetetrahydrofuran-2,2-dioxo-1,6-hexamethylene tetrahydrofuran) preparedaccording to the synthesis described in U.S. Pat. No. 4,093,709.

EXAMPLE 10

A dispenser system is prepared as follows: first, the body section of acapsule is positioned with its mouth in an upright position, and a densestainless steel element inserted into the hemipherical end of thecapsule. The dense element is machined and its shape made to match theinternal shape of the capsule. Next, a layer of an expandable, swellablecomposition is charged on top of the dense element. The compositioncomprises 25% by weight of sodium chloride and 75% by weight ofpoly(ethylene oxide) having a molecular weight of 200,000. Theexpandable forming ingredients are blended in a commercial blender withheat for 20 minutes to yield a homogeneous composition. The warmcomposition is charged into the capsule forming a layer that occupiesabout 1/3 of the capsule, next a pharmaceutical carrier comprising anactive agent is charged into the opened capsule. Next, 90 g ofpolylactide having a molecular weight of about 40,000 is dissolved inxylene and 3.5% levamisole is added thereto. The blend is charged intothe capsule to form a homogeneous mass and vacuum dried at 60° C. Then,a solution of cellulose acetate, 15 wt %, with an acetyl content of39.8%, is prepared in a methylene chloride methanol solvent system andthe outside surface of the capsule coated with a semipermeable wallwhile maintaining the mouth open. The wall is applied by dipping it intothe coating solution for 15 times, first for a 5 second dip, then fortwo ten second dips, then for a 30 second dip and then for 1 minute perdip with an intervening 5 minute drying period. Following the dippingthe delivery dispenser is dried at room temperature, 72° F., about 22°C., for 5 days. The procedure applies about a 2 mm thick semipermeablewall.

EXAMPLE 11

A dispenser is provided comprising a tube-shaped walled dispensercomprising an opened end and a closed end. The wall comprises 50%cellulose acetate butyrate, 45% poly(sulfone) and 5% citric acid esterselected from the group consisting of acetyl tributyl citrate and acetyltri-2-ethyhexyl citrate. The pharmaceutically acceptable carriercomprises the polyhydroxyacetic ester, polyglycolic acid, having thebeneficial agent impramine hydrochloride dispersed therein. The spaceconsuming means comprises poly(ethylene oxide) having a molecular weightof about 3,000,000 and 30% by weight of potassium chloride.

EXAMPLE 12

A dispenser 10 is provided according to claim 10, wherein the dispensercomprises a hydrophilic expandable member comprising a 70:30 ratio ofsodium carboxymethylcellulose to sodium chloride, lubricated with 1%magnesium stearate compressed using 10,000 lbs of force in a Carver®laboratory press.

EXAMPLE 13

A dispenser 10 was made for ascertaining the release rate profileswherein the dispenser comprises an osmotic driving member that pushes astick-shaped drug composition from the dispenser. The drug compositioncomprised the insoluble drug ibuprofen, 85%. The drug stick shapedcomposition was made by wet granulation. The composition comprised 92.5%of cellulose acetate, polyethylene oxide andhydroxypropylmethylcellulose in equal amounts, then the granules wereblended in a powder of ydroxypropylcellulose and hydroxypropylmethylcellulose. The final drug stick layer comprised 85%ibuprofen, 10% hydroxypropylcellulose, 3% hydroxypropylmethylcellulose,1% polyethylene glycol.

Accompanying FIGS. 19 and 20 represent the release rate in mg/hr and thecumulative amount released in percent from a dispenser comprising a drugcomposition comprising 84.7% ibuprofen, 2.6% of cellulose acetate andpolyethylene glycol in equal percent. 10.3% hydroxypropylcellulose and2.4% hydroxypropylmethylcellulose; an osmotic push compartmentcomprising 71% polyethylene oxide and 29% sodium chloride; and a wallcomprising 80% cellulose acetate having an acetyl content of 39.8%, 10%polyethylene glycol 3350, and 10% hydroxypropylmethylcellulose. Therelease rate for the dispenser as indicated in FIGS. 19 and 20 wasmeasured in artificial intestinal fluid. FIGS. 21 and 22 depict therelease rate for the dispenser in operation in artificial gastric fluid.

FIGS. 23 and 24 depict the release rate pattern for a dispenser inartificial gastric fluid. The drug composition in the dispensercomprised 90 wt % acetaminophen, 2 wt % polyvinyl pyrrolidonecrosslinked, 5 wt % microcrystalline cellulose, 1 wt %polyvinylpyrrolidone and 2 wt % magnesium stearate; the osmotic drivingcomposition comprised 71 wt % polyethylene oxide having a mol. wt of5,000,000 and 29 wt % sodium chloride, and a wall comprising 90 wt %cellulose acetate having an acetyl content of 39.8% and 10% polyethyleneglycol having a mol. wt of 3350.

Inasmuch as the foregoing specification comprises preferred embodimentsof the invention, it is understood that variation and modifications maybe made herein in accordance with the inventive principles disclosed,without departing from the scope of the invention.

We c1aim:
 1. A juxtaposed laminated arrangement useful for manufacturinga dispenser, which laminate when disposed in the dispenser and thedispenser is in operation administers a beneficial agent to a biologicalfluid environment of use, wherein the laminated arrangement comprises: afirst lamina means for changing from an initial physical state wheninside the dispenser to a different physical state when outside thedispenser, which first lamina comprises the beneficial agent andtransports the beneficial agent from the dispenser to the biologicalenvironment; and, a second lamina means for consuming space inside thedispenser, which second lamina comprises a hydrophilic composition thaton contact with fluid from the environment that enters the dispenserabsorbs the fluid and thereby exhibits a 2 to 50 fold volume increasefor consuming space.
 2. The juxtaposed laminated arrangement useful formanufacturing the dispenser for administering the beneficial agent tothe biologcal environment of use according to claim 1, wherein thelaminated arrangement comprises an additional lamina inteerposed betweenthe first lamina and second lamina, said interposed lamina means forkeeping the dispenser in the biological environment by exhibiting adensity greater than the density of the biological fluid environment ofuse.
 3. The juxtaposed laminated arrangement useful for manufacturingthe dispenser for administering the beneficial agent to the biologicalenvironment of use according to claim 1, wherein the laminatedarrangement comprises a third lamina adjacent to the first lamina, saidthird lamina means for keeping the dispenser in the biologicalenvironment by prossessing a specific gravity greater than the specificgravity of the biological fluid environment of use.
 4. A juxtaposedlaminated arrangement useful for manufacturing a dispenser foradministering a beneficial agent to a biological environment of use,wherein the laminate arrangement comprises: a first lamina means forchanging from a first physical state when disposed inside the dispenserto a second physical state outside the dispenser, which lamina comprisesa beneficial agent and is a carrier for administering the beneficialagent to the environment of use; and a second lamina means for consumingspace when disposed inside the dispenser, which second lamina meanscomprises a solute that mixes with aqueous fluid present in theenvironment of use that enters the dispenser and produces a solutionthat consumes space inside the dispenser.
 5. The juxtaposed arrangementuseful for manufacturing the dispenser for administering the biologicalagent to the biological environment of use according to claim 4, whereinthe laminated arrangement comprises a third lamina adjacent to thesecond lamina, said third lamina means for keeping the dispenser in thebiological environment by possessing a specific gravity greater than thespecific gravity of the biological fluid environmnt of use.
 6. Thejuxtaposed laminated arrangement useful for manufacturing the dispenserfor administering a biological agent to a biological environment of useaccording to claim 4, wherein the laminated arrangement comprisesanother lamina between the first and second laminae, said other laminacomprising a dense composition having a density greater than 1.2.